Methods for the synthesis of dioxoalkanoic acid compounds

ABSTRACT

The invention relates to improved methods of producing aryl dioxoalkanoic acid compounds and derivatives useful as intermediates for diarylpyrrole therapeutic agents by the alcoholysis of benzoylcyclohexanone ketal compounds.

FIELD OF THE INVENTION

[0001] The present invention is directed to methods for the synthesis ofdioxoalkanoic acid compounds and derivatives useful as intermediates fordiarylpyrrole therapeutic agents. More particularly, the presentinvention is directed to the treatment of benzoylcyclohexanone compoundswith an alcohol to provide improved yields of purified7-aryl4,7-dioxoheptanoic acid derivatives.

BACKGROUND OF THE INVENTION

[0002] Aryl dioxoalkanoic acid compounds are useful intermediates forthe synthesis of diarylpyrrole alkanoic acid therapeutic agents. U.S.Pat. No. 5,219,856 describes a process for preparing pyrrole compoundswith activity as angiotensin-II inhibitors. U.S. Pat. No. 5,032,590describes intermediate diphenyl isopropylpyrroles used to preparesubstituted pyrrole compounds.

[0003] WO 9825896 and Collins, P. W., et al., 1,2-Diarylpyrroles asPotent and Selective Inhibitors of Cyclooxygenase-2, J. Med Chem.,1997,40, 1619-1633 disclose the preparation of 7-aryl-4,7-dioxoheptanoic acidcompounds of the formula:

[0004] from acetophenones and furfural. These diketones have been usedto prepare diarylpyrrole alkanoic acid therapeutic agents of theformula:

[0005] These references, however, teach the preparation of the diketonecompounds using starting materials and processes that differ from thatof the present invention and having yields of about 33%.

[0006] Diketone compounds have also been produced from aryloxo andaryldioxo pentanoic, hexanoic and heptanoic acid compounds. Kapoor, V.M., et al., Steroid Intermediates, Synthesis and Transformations of7-Aryl4,7-dioxoheptanoic Acids, J. Chem. Soc, Perkin, 1973, 2420-2424.This reference discloses a process of preparing the aryldioxoheptanoicacid compounds using acid hydrolysis of furfurylidene compounds whereinthe yields of the diketone compounds varied depending on thesubstituents used.

[0007] Similarly, aryl dioxoalkanoic acid compounds, such asaroyloxohexanoic acid, have been used as intermediates in thepreparation of compounds with antiinflammatory activity. Short, F. W.,et al., Synthesis and Interconversion of 6-Aroyl4-oxohexanoic Acids and5-Aryl-2-furanpropionic Acids. Antiinflammatory Agents, J. HeterocyclicChem., 1969, 6, 713-722 describes the preparation of thearoyloxohexanoic acid compounds using acid catalyzed solvolysis. Thisreference teaches a process and starting materials that result invarying amounts of the desired diketone compounds.

[0008] The current methods used to prepare dioxoalkanoic acid compoundsgenerally suffer from either the formation of the desired product in lowyield, inseparable or hard to separate mixtures of the desired productand a different product or different products entirely. An object of thepresent invention is to provide a more efficient process to preparepurified diketone compounds with improved yields.

SUMMARY OF THE INVENTION

[0009] The present invention is directed to an efficient method for thesynthesis of purified diketone compounds with improved yields. Theprocess involves the treatment of benzoylcyclohexanone ketal compoundswith an alcohol to unexpectedly produce mono-protected 1,4-diketonecompounds such as 7-aryl-7,4-dioxoheptanones with surprisingly improvedyields. More particularly, the invention provides a method of preparinga diketone compound of the general formula (I):

[0010] wherein:

[0011] R¹ is independently selected from the group consisting ofhydrogen, halogen, —S—CH₃, —SO—CH₃, —SO₂—CH₃, —SO₂—NH₂,(C₁-C₆)alkyl orsubstituted (C₁-C₆)alkyl;

[0012] wherein the alkyl substituents are selected from —S—CH₃, —SO—CH₃,—SO₂—CH₃ or —SO₂—NH₂, (C₁-C₆)alkoxy, cycloalkyl, aryl, aralkyl, nitro,amino, hydroxy or trifluoro;

[0013] R² is independently selected from the group consisting of(C₁-C₆)alkyl or substituted (C₁-C₆)alkyl; and,

[0014] n is an integer selected from 1, 2 or 3; which method comprises,treatment of a compound of the general formula (II):

[0015] with an alcohol, wherein R¹ is as described above, to provide thediketone compounds of the general formula (I). Preferably, thealcoholysis is carried out in refluxing alcohol. More preferably, thealcoholysis of the compound of the general formula (II) is carried outin the presence of a catalytic amount of sodium methoxide.

[0016] In an additional method of synthesis embodied in this invention,purified 7-aryl4,7-dioxoheptanoic acid compounds of the general formula(III) are produced with improved yields;

[0017] wherein R¹, R² and n are as recited above; which methodcomprises, transketalyzing or mildly hydrolyzing a diketone compound ofthe general formula (I) to prepare a 7-aryl4,7-dioxoheptanoic acidcompound of the general formula (III).

[0018] Aryl dioxoalkanoic acid compounds of the general formula (III)are demonstrated as useful intermediates in the preparation ofdiarylpyrrole therapeutic compounds of the general formula (IV), such as1,5-diaryl-1H-pyrrole-2-propionic acids known to possessantiinflammatory activity;

[0019] wherein;

[0020] wherein R¹ and R² are as recited above; and,

[0021] R³ is independently selected from the group consisting ofhydrogen, halogen, —S—CH₃, —SO—CH₃, —SO₂—CH₃, —SO₂—NH₂, (C₁-C₆)alkyl orsubstituted (C₁-C₆)alkyl;

[0022] wherein the alkyl substituents are selected from —S—CH₃, —SO—CH₃,—SO₂—CH₃ or —SO₂—NH₂, (C₁-C₆₈)alkoxy, cycloalkyl, aryl, aralkyl; nitro,amino, hydroxy or trifluoro;

[0023] and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0024] Relative to the above generic description, certain compounds ofthe general formulae (I) and (III) are preferred. Particularly preferredembodiments are those compounds wherein;

[0025] R¹ is independently selected from the group consisting ofhydrogen, halogen, —S—CH₃, —SO—CH₃, —SO₂—CH₃, —SO₂—NH₂ or (C₁-C₄)alkyl;

[0026] R² is independently selected from the group consisting of(C₁-C₄)alkyl or substituted (C₁-C₄)alkyl; and,

[0027] n is an integer selected from 2 or 3;

[0028] and the pharmaceutically acceptable salts thereof.

[0029] Definitions

[0030] The terms used in describing the invention are commonly used andknown to those skilled in the art. However, the terms that could haveother meanings are hereinafter defined. These definitions apply to theterms as they are used throughout this specification, unless otherwiselimited in specific instances, either individually or as part of alarger group.

[0031] Accordingly, the term “alkyl” refers to straight or branchedchain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms,preferably 1 to 6 carbon atoms. “Independently” means that when thereare more than one substituent, the substituents may be different. Theterm “alkoxy” refers to O-alkyl where alkyl is as defined supra.

[0032] Unless otherwise specified, the term “substituted alkyl” refersto an alkyl group substituted by, for example, one to four substituents,such as, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy,cycloalkyl, cycloalkyoxy, heterocylooxy, oxo, alkanoyl, aryloxy,alkanoyloxy, amino, alkylamino, arylamino, aralkylamino,cycloalkylamino, heterocycloamino, disubstituted amines in which the 2amino substituents are selected from alkyl, aryl or aralkyl,alkanoylamine, aroylamino, aralkanoylamino, substituted alkanoylamino,substituted arylamino, substituted aralkanoylamino, thiol, alkylthio,arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono,arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,sulfonamido (e.g. SO₂NH₂), substituted sulfonamido, nitro, cyano,carboxy, carbamyl (e.g. CONH₂), substituted carbamyl (e.g.CONH alkyl,CONH aryl, CONH aralkyl or cases where there are two substituents on thenitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl,substituted aryl, guanidino and heterocyclos, such as indolyl,imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyland the like. Where noted above that the substituent is furthersubstituted, such substitutions will be with halogen, alkyl, alkoxy,aryl or aralkyl.

[0033] The term “halogen” or “halo” refers to fluorine, chlorine,bromine and iodine.

[0034] The term “aryl” refers to monocyclic or bicyclic aromatichydrocarbon groups having 6 to 12 carbon atoms in the ring portion, suchas phenyl, naphthyl, biphenyl and diphenyl and diphenyl groups, each ofwhich may be substituted.

[0035] The term “aralkyl” refers to an aryl group bonded directlythrough an alkyl group, such as benzyl.

[0036] The term “substituted aryl” refers to an aryl group substitutedby, for example, one to four substituents such as alkyl, substitutedalkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy,cycloalkyl, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino,alkylamino, aralkylamino, cycloalkylamino, heterocycloamino,dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio,heterocyclothio, ureido, nitro, nitrile, cyano, carboxy, carboxyalkyl,carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl,sulfonamido, aryloxy, alkoxycarbonyl, nitrile, furyl and the like. Thesubstitutent may be further substituted by halo, hydroxy, alkyl, alkoxy,alkoxycarbonyl, nitrile, aryl, aryloxycarbonyl, substituted aryl,substituted alkyl, aralkyl, heterocyclyl and substituted heterocyclyl.

[0037] The term “cycloalkyl” refers to optionally substituted, saturatedcyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and3 to 7 carbons per ring which may be further fused with an unsaturatedC₃ to C₇ carbocyclic ring. Exemplary groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents includeone or more alkyl groups as described above or one or more groupsdescribed above as alkyl substituents.

[0038] Exemplary substituents include one or more alkyl groups asdescribed above or one or more groups described above as alkylsubstituents.

[0039] The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

[0040] Certain abbreviations used throughout this specification,particularly the Schemes and Examples, have the following meanings,unless specifically indicated otherwise: EtOH Ethanol h hour LiHMDSLithium hexamethyldisilazide MeOH Methanol min Minutes NaOMe Sodiummethoxide rt Room temperature THF Tetrahydrofuran

[0041] General Synthetic Methods

[0042] Representative compounds of the present invention are synthesizedin accordance with the general method described below and illustrated inthe schemes. Since the schemes are illustrations, the invention shouldnot be construed as being limited by the chemical reactions andconditions expressed.

[0043] Various publications are cited throughout the description forthis general scheme. The disclosure of these publications is herebyincorporated by reference into this application to describe more fullythe state of the art to which this invention pertains.

[0044] Scheme 1 illustrates the preparation of benzoylcyclohexanoneCompound 1b and subsequent methanolysis to the diarylpyrrole Compound 1ewith improved yields. The cyclohexane-1,4-dione-monoethyleneglycol ketalCompound 1a is acylated under the conditions of Seebach, D., et al.,Helvetica Chimica Acta, 1981, 64, 3, 716, which provides the diketoneCompound 1b. The ring of the benzoylcyclohexanone Compound 1b may beopened to produce Compound 1c using refluxing methanol or, preferably,methanol at rt (room temperature) in the presence of a catalytic (cat)amount of sodium methoxide. The catalyzed reactions are complete in afew hours, while uncatalyzed reactions require several days. Double acidhydrolysis of the ketal-ester Compound 1c with equal portions of THF and3N HCl over several hours at rt cleanly afford the diketo-acid Compound1d. There was no evidence for the formation of yield-lowering furanside-products known in the art except after prolonged reaction times inacid. Heterocyclization of Compound 1d to the pyrrole Compound 1e wascarried out in refluxing methanol, with or without a p-toluenesulfonicacid (ptsa) catalyst, and was complete in about 2 days. The catalyzedreactions yield methyl ester compounds; the reactions without ptsa formthe acid compounds.

[0045] Scheme 2 illustrates the preparation of sulfoxide Compound 2bfrom sulfide Compound 2a in low yield by oxidation with oxone. Nosulfone was observed under these conditions. Sulfone Compound 2c wasprepared using 4-methanesulfonylaniline in the cyclization (no ptsa).Compound 2c can be subsequently hydrolyzed to the acid Compound 2d. Thecyclization reactions produce comparable yields for either the ester oracid compounds.

[0046] Yields for the compound types prepared in Scheme 1 and Scheme 2are compiled in Tables 1 to 4. TABLE 1 Compound Yields

Compound 1b; Scheme 1 R¹ % Yield Cl 74 F 80 SO₂Me 60

[0047] TABLE 2 Compound Yields

Compound 1c; Scheme 1 R¹ R² % Yield Cl Me 96 F Me 81 SO₂Me Me 24

[0048] TABLE 3 Compound Yields

Compound 1d; Scheme 1 R¹ R² % Yield Cl H 98 F H 100  SO₂Me H 57

[0049] TABLE 4 Compound Yields

Compound 2a-2d; Scheme 2 Compound 1e; Scheme 1 R¹ R² R³ % Yield F H SMe67 F H SOMe 15 F Me SO₂Me 80 F H SO₂Me 89 F Me SMe 71 SO₂Me H F 30 Cl MeSO₂NH₂ 96 Cl H SO₂NH₂ 88

[0050] The foregoing reactions are performed in a solvent appropriate tothe reagents and materials employed and suitable for the transformationbeing effected. It is understood by those skilled in the art of organicsynthesis that the various functionalities present on the molecule mustbe consistent with the chemical transformations proposed. This willfrequently necessitate judgment as to the order of synthetic steps,protection of reactive groups, and selection of reaction conditions.Reaction conditions compatible with the substituents employed will beapparent to one skilled in the art, as will be the selection ofprotecting groups where needed.

[0051] From compounds of the general formula (II), it is evident thatsome of the compounds of the invention may have one or more asymmetricalcarbon atoms in their structure. It is intended that the presentinvention include within its scope the stereochemically pure isomericforms of the compounds as well as their racemates. Stereochemically pureisomeric forms may be obtained by the application of art knownprinciples. Diastereoisomers may be separated by physical separationmethods such as fractional crystallization and chromatographictechniques, and enantiomers may be separated from each other by theselective crystallization of the diastereomeric salts with opticallyactive acids or bases or by chiral chromatography. Pure stereoisomersmay also be prepared synthetically from appropriate stereochemicallypure starting materials, or by using stereospecific reactions.

[0052] Suitable pharmaceutical salts are those of inorganic or organicacids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, nitric acid, phosphoric acid, acetic acid, succinic acid,oxalic acid, malic acid and the like. Suitable salts are also those ofinorganic or organic bases, such as KOH, NaOH, Ca(OH)₂, Al(OH)₃,piperidine, morpholine, ethylamine, triethylamine and the like.

[0053] Also included within the scope of the invention are the hydratedforms of the compounds that contain various amounts of water, forinstance, the hydrate, hemihydrate and sesquihydrate forms.

SPECIFIC SYNTHETIC EXAMPLES

[0054] The synthesis of specific, representative compounds of thepresent invention is presented in detail in the following example. Thisexample is intended to illustrate a method of synthesis and is notintended to limit the scope of the claims in any way. Moreover, noattempt has been made to further optimize the yield obtained in thisreaction. It would be obvious to one skilled in the art that variationsin reaction time, temperature, solvents and/or reagents could increasethe yields.

Example1

[0055]

[0056] The diketone Compound 1a (141 mg, 0.477 mMol) was dissolved inanhydrous methanol (2 mL) and treated with a NaOMe solution (25%, 0.20mL) in anhydrous methanol at about rt. After about 1 h, the mixture wasdiluted with ethyl acetate (50 mL). The pH of the solution was carefullyadjusted to about pH 2 with 2N HCl. Water (50 mL) was added and theethyl acetate layer was dried with anhydrous sodium sulfate andfiltered. Evaporation of the solvent afforded Compound 1b (150 mg, 96%yield) as a light tan solid.

We claim:
 1. A method of preparing a diketone compound of the generalformula (I):

wherein: R¹ is independently selected from the group consisting ofhydrogen, halogen, —S—CH₃, —SO—CH₃, —SO₂—CH₃, —SO₂—NH₂, (C₁-C₆)alkyl orsubstituted (C₁-C₆)alkyl; wherein the alkyl substituents are selectedfrom —S—CH₃, —SO—CH₃, —SO₂—CH₃ or —SO₂—NH₂, (C₁-C₆)alkoxy, cycloalkyl,aryl, aralkyl, nitro, amino, hydroxy or trifluoro; R² is independentlyselected from the group consisting of (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl; and, n is an integer selected from 1, 2 or 3; which methodcomprises, treatment of a compound of the general formula (II):

with an alcohol, wherein R¹ is as described above, to provide thediketone compounds of the general formula (I).
 2. A method according toclaim 1, wherein the alcoholysis is performed in the presence of acatalytic amount of sodium methoxide.
 3. A method according to claim 1,wherein the alcoholysis is performed in refluxing alcohol.
 4. A compoundselected from those of the formula:

wherein: R¹ is independently selected from the group consisting ofhydrogen, halogen, —S—CH₃, —SO—CH₃, —SO₂—CH₃, —SO₂NH₂, (C₁-C₆)alkyl orsubstituted (C₁-C₆)alkyl; wherein the alkyl substituents are selectedfrom —S—CH₃, —SO—CH₃, —SO₂—CH₃ or —SO₂—NH₂, (C₁-C₆)alkoxy, cycloalkyl,aryl, aralkyl, nitro, amino, hydroxy or trifluoro; R² is independentlyselected from the group consisting of (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl; and, n is an integer selected from 1, 2 or 3; and thepharmaceutically acceptable salts thereof.
 5. A compound according toclaim 4, wherein; R¹ is independently selected from the group consistingof hydrogen, halogen, —S—CH₃, —SO—CH₃, —SO₂—CH₃, —SO₂—NH₂ or(C₁-C₄)alkyl; R² is independently selected from the group consisting of(C₁-C₄)alkyl or substituted (C₁-C₄)alkyl; and, n is an integer selectedfrom 2 or 3; and the pharmaceutically acceptable salts thereof.
 6. Amethod of producing 7-aryl4,7-dioxoheptanoic acid compounds of thegeneral formula (III):

wherein R¹ is independently selected from the group consisting ofhydrogen, halogen, —S—CH₃, —SO—CH₃, —SO₂—CH₃, —SO₂—NH₂, (C₁-C₆)alkyl orsubstituted (C₁-C₆)alkyl; wherein the alkyl substituents are selectedfrom —S—CH₃, —SO—CH₃, —SO₂—CH₃ or —SO₂—NH₂, (C₁-C₆)alkoxy, cycloalkyl,aryl, aralkyl, nitro, amino, hydroxy or trifluoro; R² is independentlyselected from the group consisting of (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl; and, n is an integer selected from 1, 2 or 3; which methodcomprises, transketalyzing or mildly hydrolyzing a diketone compound ofthe general formula (I) to prepare a 7-aryl-4,7-dioxoheptanoic acidcompound of the general formula (III).
 7. A compound selected from thoseof the formula:

wherein: R¹ is independently selected from the group consisting ofhydrogen, halogen, —S—CH₃, —SO—CH₃, —SO₂—CH₃, —SO₂—NH₂, (C₁-C₆)alkyl orsubstituted (C₁-C₆)alkyl; wherein the alkyl substituents are selectedfrom —S—CH₃, —SO—CH₃, —SO₂—CH₃ or —SO₂—NH₂, (C₁-C₆)alkoxy, cycloalkyl,aryl, aralkyl, nitro, amino, hydroxy or trifluoro; R² is independentlyselected from the group consisting of (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl; and, n is an integer selected from 1, 2 or 3; and thepharmaceutically acceptable salts thereof.
 8. A compound according toclaim 7, wherein; R¹ is independently selected from the group consistingof hydrogen, halogen, —S—CH₃, —SO—CH₃, —SO₂—CH₃, —SO₂—NH₂ or(C₁-C₄)alkyl; R² is independently selected from the group consisting of(C₁-C₄)alkyl or substituted (C₁-C₄)alkyl; and, n is an integer selectedfrom 2 or 3; and the pharmaceutically acceptable salts thereof.
 9. Acompound according to claim 5 of the formula:


10. A compound according to claim 5 of the formula:


11. A compound according to claim 5 of the formula:


12. A compound according to claim 8 of the formula:


13. A compound according to claim 8 of the formula:


14. A compound according to claim 8 of the formula: